1. Technical Field
The present invention generally relates to an improved process for preparing strontium ranelate and its hydrates.
2. Description of the Related Art
Strontium ranelate, the distrontium salt of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, is represented by the structure of Formula I.
Strontium ranelate has very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties, making this compound useful in the treatment of bone diseases.
EP 0415850 and related U.S. Pat. No. 5,128,367 (“the '367 patent”) disclose divalent metal salts of 2-[N,N-di(carboxymethyl)amino]-3-cyano4-carboxymethylthiophene-5-carboxylic acid such as strontium ranelate and its tetrahydrate, heptahydrate and octahydrate. The '367 patent further discloses the synthesis of strontium ranelate from the tetraester compound of Formula II:
wherein the process involves heating the tetraester compound of Formula II at reflux in an aqueous alcoholic medium in the presence of a sodium hydroxide solution and then hydrolyzing the heated solution in an acidic medium to provide an acid of Formula IV.
The acid of Formula IV is thereafter converted into its sodium salt and then converted into strontium ranelate using strontium hydroxide or strontium chloride in water.
Another process for preparing strontium ranelate disclosed in the '367 patent includes heating the tetraester compound of Formula II at reflux in a 50/50 mixture by volume of a normal sodium hydroxide solution and ethanol, distilling off the solvents to obtain the tetrasodium salt which is thereafter treated with an aqueous chloride solution of, for example, strontium dichloride.
Yet another process for preparing strontium ranelate disclosed in the '367 patent includes heating the tetraester compound of Formula II at reflux in an aqueous alcoholic medium with a hydroxide, for example, strontium hydroxide. The process disclosed in the '367 patent requires heating at higher temperature, which is believed to generate impurities.
However, industrial production of a compound such as strontium ranelate requires a detailed study of all the reaction steps and of the selection of the starting material reagents and solvents in order to obtain an optimum yield and purity.
Accordingly, there remains a need for a simple industrial process for preparing strontium ranelate and its hydrates in relatively high purity and yield on a commercial scale in a convenient and cost efficient manner. Additionally, it would be desirable to provide a process for preparing strontium ranelate and its hydrates in a shorter reaction time and under mild reaction conditions in which the isolation of the free acid or sodium salt intermediates are completely avoided.